title: Identification of N-substituted 8-azatetrahydroquinolone derivatives as selective and orally active M(1) and M(4) muscarinic acetylcholine receptors agonists.
abstract: We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, Suita, Osaka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takai
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Konishi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suwa
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Uruno
authors.forename: Harumi
authors.initials: H
authors.lastname: Matsuda
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nakako
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Sakai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Gakuji
authors.initials: G
authors.lastname: Hashimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uematsu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kiyoshi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001372:Aza Compounds; D006873:Hydroquinones; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; C031927:hydroquinone
keywords: 8-Azatetrahydroquinolone; Antipsychotic agents; M(1) muscarinic acetylcholine receptor; M(4) muscarinic acetylcholine receptor; Schizophrenia; Selective agonist